Andes virus (ANDV) is a hantavirus (HV) that is uniquely spread person to person and causes 35% fatal respiratory distress termed HV pulmonary syndrome (HPS). There are no therapeutics for reducing or resolving the severity of HFRS or HPS diseases. HVs are segmented negative-stranded RNA viruses that, like Influenza A virus (IAV), contain a viral endonuclease which cleaves cellular mRNAs in order to prime viral mRNA transcription (cap- snatching). The cap snatching endonuclease of IAV was recently shown to be a therapeutic target potently inhibited by Baloxavir (BXA; Xofluza), a novel clinically approved IAV antiviral. This established the endonuclease as a target for antiviral drug development and suggested the potential for therapeutically targeting conserved endonucleases of ANDV and other HVs. Comparisons of crystal structures of IAV and ANDV endonucleases revealed a highly conserved active site comprised of essential catalytic residues. This suggested the potential for BXA to bind and inhibit the ANDV endonuclease. We expressed and purified functionally active ANDV Endo-K44A protein and in initial studies found that BXA inhibited Endo-directed RNA cleavage and ANDV infection of VeroE6 cells with IC50s of ~500 nM. Our in silico analysis of ANDV Endo-BXA complexes revealed that BXA is well accommodated in the ANDV Endo active site and that BXA docking to the ANDV catalytic pocket is conserved. These findings suggest that BXA derivatives with lower IC50s may bind the ANDV active site and inhibit the ANDV Endo at therapeutic levels or serve as leads for therapeutic advancement. In defining BXA as an IAV inhibitor, Shionogi Pharm. generated 809 BXA derivatives which are available to us and which we propose analyzing as ANDV endonuclease and viral replication inhibitors. We will dock BXA derivatives in silico with existing crystal structures of the ANDV Endo domain to delineate best fit inhibitors. We test BXA derivatives for efficacy in inhibiting ANDV endonuclease directed cap-dependent and cap-independent RNA cleavage and for restricting ANDV replication and EC permeability. The success of BXA therapeutically targeting the IAV endonuclease and the similarity of the IAV and ANDV endonuclease active sites strongly rationalize the HV endonuclease as a viable therapeutic target and BXA derivatives as potential ANDV antivirals. We hypothesize that the HV endonuclease is a potential target of existing BXA derivatives with therapeutic potential as a HV antiviral that reduces replication and inhibits EC permeability.